C5L2 is a enigmatic serpentine receptor that is co-expressed with the C5a receptor on many cell types including PMN neutrophils. The absence of coupling of C5L2 to G proteins, as well as our preliminary data, suggest that this receptor does not transduce signals like the classical C5a receptor, but may instead modulate the biological activity of C5a. In vivo studies support the concept that C5L2 acts as a decoy receptor. Alternatively, it may affect function through formation of intermolecular complexes (eg heterodimers) with the C5aR. A distinct signaling mechanism may also exist for C5L2. Mice bearing a targeted deletion of C5L2 exhibit enhanced biological activity of C5a/C5adesArg- Thus, the biological function of C5L2 appears to be to limit the proinflammatory response to the anaphylatoxin utilizing one or more of the mechanisms described above. Accordingly, up-regulation of C5L2 may be of benefit in inflammatory states driven by C5a, potentially in sepsis, asthma, cystic fibrosis and chronic obstructive lung disease. Other potential actions of C5L2 that have been proposed include up-regulation of the anti- inflammatory neuroendocrine axis, regulation of triglyceride synthesis, and homing of stem cells to bone marrow. The tools we have created in the mouse will allow for proof or rejection of these responses as mediated by C5L2. In the current renewal application, we propose to characterize the functional interactions of C5L2 with its ligands, C5a and C5adeSArg, and its relationship with the classical C5a receptor through the following Specific Aims: 1)we will characterize the phenotype of C5L2-/- mice in the na'i've state, in models of immune complex injury, septic shock, and Th1/Th2 inflammation. Wewill further investigate the role of C5L2 in triglyceride synthesis and regulation of the adrenocortical axis. 2) We will generate mice in which C5L2 is over-expressed in the lung, and mice in which human C5aR is expressed in place of murine CSaR, allowing pharmacological blockade of the C5aR with receptor antagonists. These animals will be used to evaluate the anti-inflammatory actions of C5L2 in immune complex injury and septic shock. 3) We will determine the structure of C5L2 as a C5a binding protein. Finally, 4) we will examine potential alternative signaling mechanisms mediated by binding of C5a/C5adeSArg to C5L2. Successful completion of this research program will increase our knowledge relevant to acute and chronic lung injury. Potential treatment options for these diseases could arise through translational research inspired by this proposal.